This application relates to sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same.
1. Background Art
An extracellular matrix consists of collagen, proteoglycan, etc., has a function to support tissues, and plays a role in a maintaining of a cell functions, for example propagation, differentiation, adhesion, or the like. Matrix metalloproteinases (MMP) such as gelatinase, stromelysin, collagenase, and the like have an important role in degradation of an extracellular matrix, and these enzymes work for growth, tissue remodeling, etc. under physiological conditions. Therefore, it is considered that these enzymes participate in progression of various kind of diseases involving breakdown and fibrosis of tissues, such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontitis, metastasis and invasion of tumor, and virus infection (for example, HIV infection). At the present time, it is not clear which enzyme participates in the above diseases seriously, but it is considered that these enzymes at least participate in tissue breakdown. As metalloproteinase inhibitors of amino acid derivatives, for example hydroxamic acid derivatives of amino acids (JP-A-6-2562939), carboxylic acid derivatives of amino acid and/or their hydroxamic acid derivatives (WO95/35276), etc. are disclosed.
2. Disclosure of Invention
If it is able to inhibit the activity of MMP, it is considered that MMP inhibitors contribute to an improvement and prevention of the above diseases caused by or related to its activity. Therefore, development of MMP inhibitors has long been desired.
In the above situation, the inventors of the present invention found that a kind of sulfonamide derivatives have strong activity to inhibit MMP.
The present invention relates to a composition for inhibiting metalloproteinase which contains a compound of the formula I: 
wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R4 is a bond, xe2x80x94(CH2)mxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94N(RA)xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94SO2xe2x80x94NHxe2x80x94Nxe2x95x90CHxe2x80x94, or tetrazol-diyl; R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or lower alkyl; Y is xe2x80x94NHOH or xe2x80x94OH; and m is 1 or 2; provided R2 is hydrogen atom when Y is xe2x80x94NHOH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
Mentioned in more detail, the invention relates to the following a)-b), 1)-16), and A)-C).
a) A composition for inhibiting metalloproteinase which contains a compound of the formula I: 
xe2x80x83wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R4 is a bond, xe2x80x94(CH2)mxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94N(RA)xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94SO2xe2x80x94NHxe2x80x94Nxe2x95x90CHxe2x80x94, or tetrazol-diyl; R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or lower alkyl; Y is xe2x80x94NHOH or xe2x80x94OH; and m is 1 or 2; provided R2 is hydrogen atom when Y is xe2x80x94NHOH, R5 is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is COxe2x80x94NHxe2x80x94 or xe2x80x94NHxe2x80x94COxe2x80x94, R5 is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heteroarylene and R4 is tetrazol-diyl, R5 is lower alkyl, aryl substituted by lower alkyl or optionally substituted aryl, or heteroaryl substituted by lower alkyl or optionally substituted aryl when R3 is optionally substituted arylene and R4 is a bond, both of R3 and R4 are not a bond at the same time, and R4 is not xe2x80x94Oxe2x80x94 when R3 is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
b) A composition for inhibiting metalloproteinase as mentioned above, which is a composition for inhibiting type-IV collagenase.
Preferred embodiment of the present invention are as follows.
1) A compound of the formula I: 
xe2x80x83wherein R1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R2 is hydrogen atom, optionally substituted lower alkyl optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R3 is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R4 is a bond, xe2x80x94(CH2)mxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, N(RA)xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94SO2xe2x80x94NHxe2x80x94Nxe2x95x90CHxe2x80x94, or tetrazol-diyl; R5 is optionally substituted lower alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; RA is hydrogen atom or lower alkyl; Y is xe2x80x94NHOH or xe2x80x94OH; and m is 1 or 2; provided R2 is hydrogen atom when Y is xe2x80x94NHOH, R5 is optionally substituted aryl or optionally substituted heteroaryl when R3 is optionally substituted arylene or optionally substituted heterolene and R4 is xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94NHxe2x80x94COxe2x80x94 (when R3 is phenylene and R4 is xe2x80x94COxe2x80x94NHxe2x80x94, R1 is not methyl or phenyl and R5 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl), R5 is lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl when R3 is alkyl, optionally substituted arylene or optionally substituted heteroarylene and R4 is tetrazol-diyl, R5 is lower alkyl, aryl substituted with lower alkyl or optionally substituted aryl, or heteroaryl substituted with lower alkyl or optionally substituted aryl when R3 is optionally substituted arylene and R4 is a bond, both of R3 and R4 are not a bond at the same time, and R4 is not xe2x80x94Oxe2x80x94 when R3 is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
2) A compound of the formula II: 
xe2x80x83wherein R6 is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2NHxe2x80x94, or xe2x80x94SO2xe2x80x94NHxe2x80x94Nxe2x95x90CHxe2x80x94; R7 is optionally substituted aryl or optionally substituted heteroaryl; R8 and R9 are each independently hydrogen atom, lower alkoxy, or nitro; R1, R2, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
3) A compound of the formula III: 
xe2x80x83wherein R10 is xe2x80x94(CH2)mxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94N(RA)xe2x80x94, xe2x80x94NHCOxe2x80x94, or tetrazol-diyl; m is 1 or 2; R1, R2, R7, R8, R9, RA, and Y are as defined above, provided R1 is not methyl or phenyl and R7 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl when R10 is xe2x80x94NHxe2x80x94COxe2x80x94, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
4) A compound of the formula IV: 
xe2x80x83wherein R11 is a bond, xe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94; X is oxygen atom or sulfur atom, R1, R2, R7, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
5) A compound of the formula Ixe2x80x2: 
xe2x80x83wherein R1xe2x80x2 is benzyl, (indol-3-yl)methyl, (1-methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (1-acetylindol-3-yl)methyl, (1-methylsulfonylindol-3-yl)methyl, (1-alkoxycarbonyl-3-yl)methyl (for example ethoxycarbonylmethyl), or i-propyl; R2xe2x80x2 is hydrogen atom, methyl, 4-aminobutyl, or benzyl; R3xe2x80x2 is 1,4-phenylene; R4xe2x80x2 is xe2x80x94Oxe2x80x94; R5xe2x80x2 is phenyl or 4-hydroxy-phenyl; and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
6) A compound of the formula Ixe2x80x3: 
xe2x80x83wherein R1xe2x80x3 is 4-thiazolylmethyl, (indol-3-yl)methyl, (5-methoxyindol-3-yl)methyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-biphenylylmethyl, 2,2,2-trifluoroethyl, 2-phenylethyl, benzyl, i-propyl, 4-nitrobenzyl, 4-fluorobenzyl, cyclohexylmethyl, (1-methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (5-fluoroindol-3-yl)methyl, (pyridin-4-yl)methyl, (benzothiazol-2-yl)methyl, (phenyl)(hydroxy)methyl, phenyl, carboxymethyl, 2-carboxyethyl, hydroxymethyl, phenylmethoxymethyl, 4-carboxybenzyl, (benzimidazol-2-yl)methyl, (1-methylsulfonylindol-3-yl)methyl, or (1-ethoxycarbonylindol-3-yl)methyl; R2xe2x80x3 is hydrogen atom; R3xe2x80x3 is 1,4-phenylene; R4xe2x80x3 is a bond; R5xe2x80x3 is phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methylthiophenyl, 4-biphenylyl, 2-thienyl, benzoxazol-2-yl, benzothiazol-2-yl, or tetrazol-2-yl; and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
7) A compound of the formula V: 
xe2x80x83wherein R12 is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94; R1, R2, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
8) A compound of the formula VI: 
xe2x80x83wherein R2, R8, and R9 are as defined above, R13 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; and R14 is optionally substituted aryl, or optionally substituted heteroaryl; provided R13 is not methyl or phenyl and R14 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof
9) A compound of the formula VII: 
xe2x80x83wherein R1, R2, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
10) A compound of the formula VIII: 
xe2x80x83wherein R1, R2, R7, and R11 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
11) A compound of the formula VIII: 
xe2x80x83wherein R1, R2, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
12) A compound of the formula X: 
xe2x80x83wherein R12 is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94; R1, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
13) A compound of the formula XI: 
xe2x80x83wherein R8, R9, R13, and R14 are as defined above, provided R13 is not methyl or phenyl and R14 is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
14) A compound of the formula XII: 
xe2x80x83wherein R1, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
15) A compound of the formula XIII: 
xe2x80x83wherein R1, R7, and R11 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
16) A compound of the formula XIV: 
xe2x80x83wherein R1, R7, R8, and R9 are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.
A compound of the invention is more specifically illustrated below:
A) The compound of any one of above 1) to 16), wherein R1, R1xe2x80x2, R1xe2x80x3, and R13 are i-propyl, benzyl, or (indol-3-yl) methyl.
B) The compound of any one of above 1) to 4) and 7) to 16), wherein R5, R7, and R14 are phenyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, alkylthio, and alkyl.
C) The compound of any one of above 1) to 16), wherein a configuration of asymmetric carbon atoms bonding with R1, R1xe2x80x2, R1xe2x80x3, and R13 is R configuration.
Further, this invention relates to a pharmaceutical composition, a composition for inhibiting metalloproteinase, and a composition for inhibiting type IV collagenase which contain the compound above 1) to 16) and A) to C)
All of compounds of above 1) to 16) and A) to C) have strong metalloproteinase inhibitory activity, and the following compound is more preferable: 
1) A compound wherein R1 is i-propyl, benzyl, or (indol-3-yl) methyl, R2 is hydrogen atom, R3 is 1,4-phenylene, R4 is xe2x80x94Cxe2x89xa1Cxe2x80x94, and R5 is optionally substituted phenyl.
2) A compound wherein R1 is i-propyl, benzyl, or (indol-3-yl) methyl, R2 is hydrogen atom, R3 is optionally substituted 2,5-thiophen-diyl, R4 is xe2x80x94Cxe2x89xa1Cxe2x80x94, and R5 is optionally substituted phenyl.
3) A compound wherein R1 is i-propyl, benzyl, or (indol-3-yl)methyl, R2 is hydrogen atom, R3 is 1,4-phenylene, R4 is tetrazol-diyl, and R5 is optionally substituted phenyl.
The term xe2x80x9calkylxe2x80x9d herein used means C1-C10 straight or branched chain alkyl, example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, and the like.
The term xe2x80x9clower alkylxe2x80x9d herein used means C1-C6 straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, and the like.
The term xe2x80x9cC3xe2x80x94C8 cycloalkylxe2x80x9d herein used is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The term xe2x80x9carylxe2x80x9d herein used means monocyclic or condensed ring aromatic hydrocarbons. Examples of the aryl are phenyl, naphthyl, and the like.
The term xe2x80x9caralkylxe2x80x9d herein used means the above mentioned alkyl substituted by the above mentioned aryl at any possible position. Examples of the aralkyl are benzyl, phenethyl, phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (xcex1-naphthylmethyl), anthrylmethyl (9-anthrylmethyl), and the like. Benzyl is preferred. The aryl part may optionally be substituted.
The term xe2x80x9cheteroarylxe2x80x9d herein used means a 5 to 6 membered aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring and may be fused with a carbocyclic ring or other heterocyclic ring at any possible position. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl (e.g., 2-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g., 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolizinyl), pyridyl (e.g., 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyl (e.g., 2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g., 2-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (e.g., 3-furyl), benzofuryl (e.g., 3-benzofuryl), thienyl (e.g., 2-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, and the like. The aryl part of the above heteroaryl is optionally substituted.
The term xe2x80x9cheteroarylalkylxe2x80x9d herein used means the above mentioned alkyl substituted with the above mentioned heteroaryl at any possible position. Examples of the heteroarylalkyl are thiazolylmethyl (e.g., 4-thiazolylmethyl), thiazolylethyl (e.g., 5-thiazolyl-2-ethyl), indolylmethyl (e.g., 2-indolylmethyl), imidazolylmethyl (e.g., 4-imidazolylmethyl), benzothiazolylmethyl (e.g., 2-benzothiazolylmethyl), benzopyrazolylmethyl (e.g., 1-benzopyrazolylmethyl), benzotriazolylmethyl (e.g., 4-benzotriazolylmethyl), benzoquinolylmethyl (e.g., 2-benzoquinolylmethyl), benzimidazolylmethyl (e.g., 2-benzimidazolylmethyl), pyridylmethyl (e.g., 2-pyridylmethyl), and the like. The aryl part of the above heteroaryl is optionally substituted.
The term xe2x80x9carylenexe2x80x9d herein used is exemplified by phenylene, naphthylene, and the like. Mentioned in more detail, it is exemplified by 1,2-phenylene, 1,3-phenylene,1,4-phenylene, and the like.
The term xe2x80x9cheteroarylenexe2x80x9d herein used is exemplified by thiophen-diyl,furan-diyl, pyridin-diyl, and the like, in more detail, by 2,5-thiophen-diyl, 2,5-furan-diyl, and the like.
The term xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d herein used means 5 to 6 membered non-aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, and may bind at any possible position. Examples of the non-aromatic heterocyclic group are morpholino, piperidino, pyrrolidino, and the like.
The term xe2x80x9calkoxyxe2x80x9d herein used means alkoxy of which alkyl part is the above mentioned alkyl. Examples of the alkoxy are methoxy, ethoxy, propoxy, butoxy, pentyloxy, and the like.
The term xe2x80x9clower alkoxyxe2x80x9d herein used means alkoxy of which alkyl part is the above mentioned lower alkyl. Examples of the lower alkoxy are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, and the like.
The term xe2x80x9chalogenxe2x80x9d herein used means fluoro, chloro, bromo, and iodo.
The term xe2x80x9calkylthioxe2x80x9d herein used means alkylthio whose alkyl part is the above mentioned lower alkyl. Examples of the alkylthio are methylthio, ethylthio, and the like.
Substituents for xe2x80x9coptionally substituted alkylxe2x80x9d, xe2x80x9coptionally substituted C3-C8 cycloalkylxe2x80x9d, and xe2x80x9coptionally substituted non-aromatic heterocyclic groupxe2x80x9d are hydroxy, alkoxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbony), nitro, cyano, haloalkyl (e.g., trifluoromethyl), substituted or unsubstituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), guanidino, phenyl, benzyloxy, and the like. These substituents are able to bind them at one or more of any possible positions.
Substituents for the aromatic ring of xe2x80x9coptionally substituted aryrxe2x80x9d, xe2x80x9coptionally substituted aralkylxe2x80x9d, xe2x80x9coptionally substituted heteroarylxe2x80x9d, xe2x80x9coptionally substituted heteroarylalkylxe2x80x9d, xe2x80x9coptionally substituted arylenexe2x80x9d, and xe2x80x9coptionally substituted heteroarylenexe2x80x9d are, for example, hydroxy, alkoxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy) substituted or unsubstituted amino (e.g., methylamino, dimethylamino, diethylamino, and benzylidenamino), guanidino, alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, and tert-pentyl), alkenyl (e.g., vinyl and propenyl), alkynyl (e.g., ethynyl and phenylethynyl), alkanoyl (e.g., formyl, acetyl, and propionyl), acyloxy (e.g., acetyloxy), acylamino, alkylsulfonyl (e.g., methylsulfonyl), phenyl, benzyl, an azo group (e.g., phenylazo), optionally substituted heteroaryl (e.g., 3-pyridyl), optionally substituted ureido (e.g., ureido and phenylureido), and the like. These substituents are able to bind to it at one or more of any possible position.
Compounds (Ia) and (Ib) of the invention are able to be synthesized from the corresponding xcex1-amino acids represented by the formula (XV) by means of the following 6 synthetic methods. Generally, it is possible to produce the compounds of the invention by means of the method A. Each classified type of the compounds is possible to be produced by means of methods the B to F. However, these methods are only examples to produce the compounds represented by the formula I. A compound represented by the formula I produced by any other method is included in this invention.
Method A: A general synthetic method of the compound represented by the formula I.
Method B: A synthetic method of the compound wherein and R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is xe2x80x94Cxe2x89xa1Cxe2x80x94, and R5 is optionally substituted aryl or optionally substituted heteroaryl.
Method C: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is a bond, and R5 is optionally substituted aryl or optionally substituted heteroaryl.
Method D: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is xe2x80x94COxe2x80x94NHxe2x80x94, and R5 is optionally substituted aryl or optionally substituted heteroaryl.
Method E: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is tetrazol-diyl, and R5 is optionally substituted aryl or optionally substituted heteroaryl.
Method F: A synthetic method of the compound wherein R3 is optionally substituted arylene or optionally substituted heteroarylene, R4 is xe2x80x94CHxe2x95x90CHxe2x80x94, and R5 is optionally substituted aryl or optionally substituted heteroaryl.
Details of these methods are explained as follows. 
wherein R1, R2, R3, R4, and R5 are as defined above, R15 is hydrogen atom or a carboxy protective group, R16 is a hydroxy protective group, and Hal is halogen.
Conversion of compound (XV) to compound (Ia-1) is sulfonation of an amino group of the compound (XV) (process 1). If necessary, after this reaction, N-alkylation, deprotection of a carboxyl protective group, etc. are carried out. Conversion of compound (Ia-1) to compound (Ib-1) is to obtain hydroxamic acid derivatives from carboxylic acid derivatives (process 2). To obtain compound (Ib-1) from compound (Ia-1), compound (Ia-1) may also be reacted with hydroxylamine having a hydroxyl protective group or its acidic salts to give compound (XVI) (process 3), followed by and deprotection (process 4). Conversion to sulfonyl derivatives and hydroxamic acid derivatives are able to be carried out according to an usual method. For example, an amino acid represented by the formula (XV) is reacted with a sulfonating agent such as sulfonyl halide represented by R5xe2x80x94R4xe2x80x94R3xe2x80x94SO2Hal (R3, R4, and R5 are as defined above; and Hal is halogen) and then hydroxylamine. Each process will hereinafter be described in more detail.
(Process 1)
Some of amino acids represented by the formula (XV) or its acidic salts (e.g., hydrochloride, p-toluenesulfonate, and trifluoroacetate) which are starting materials are commercially available. The other are able to be synthesized in accordance with a method described in Zikkenkagakukoza, vol. 22, IV (nihonkagakukai), J. Med. Chem. 38, 1689-1700, 1995, Gary M. sander et. al., etc. some of sulfonating agents are commercially available and the other are synthesized in accordance with a method described Shin-zikkenkagakukoza, vol. 14, 1787, 1978, Synthesis 852-854, 1986, etc. A carboxyl protective group is exemplified by esters (e.g., methyl ester, tert-butyl ester and benzyl ester). Deprotection of this protective group may be carried out by hydrolysis with acid (e.g., hydrochloride and trifluorbacetic acid) or base (e.g., sodium hydroxide) depending on the type of the group, or by catalytic reduction, e.g., under 10% palladium-carbon catalyst condition. To obtain a compound (Ib-1), the esters may directly be converted to hydroxamic acid by the method of process 2. When a compound (XV) is an amino acid wherein R15 is hydrogen atom, preferable solvents for this sulfonylation are dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, water, or mixed solvents thereof. When a compound (XV) is an amino acid wherein R15 is a protective group such as an ester, a solvent for this sulfonylation is exemplified by the above solvents and mixed solvents of water-insoluble solvents (e.g., benzene and dichloromethane) and the above solvents. A base to be used in this sulfonylation is exemplified by organic bases such as triethylamine, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and the like. Usually this reaction can be carried out at ice-cooling to room temperature. When R1, R3, R4, R5, or R15 of compound (Ia-1) contains a functional group(s) possibly interfering this sulfonylation (e.g., hydroxy, mercapto, amino, and guanidino), it can previously be protected in accordance with a method described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (Theodora W. Green (John Wiley and Sons)) and then deprotected at an appropriate process. When R2 is not hydrogen atom, compound (Ia-1) wherein R2 is hydrogen atom is further reacted with haloalkyl (e.g., methyl iodide, and ethyl iodide) or haloaralkyl (e.g., benzyl chloride, and benzyl bromide) in dimethylformamide, tetrahydrofuran, dioxane, and the like at a temperature range of ice-cooling to 80 xc2x0 C., preferably ice-cooling to room temperature, for 3-10 hours, preferably 10-20 hours to give the desired Nxe2x80x94R2 derivative.
(Process 2)
A hydroxylamine is reacted with compound (Ia-1) or its reactive derivatives to give hydroxamic acid derivatives (Ib-1). A hydroxylamine is usually used as its acidic salts (e.g., hydrochloride, and phosphate, sulfate: commercially available) in the presence of a base. A base to be used in this reaction is exemplified by organic bases such as triethylamine, N, N-dimethylaniline, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc. When compound (Ia-1) is used as a starting material of conversion to hydroxamic acid, this reaction is carried out in the presence of a peptide condensing agent (e.g., dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,Nxe2x80x2-carbonyldiimidazole, or a mixture of one of the above agents with 1-hydroxybenzotriazole, N-hydroxy sucinicimide, etc.). A solvent for this reaction may be dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, water, and mixed solvent thereof This reaction is carried out at xe2x88x9220xc2x0 C. to 40xc2x0 C., preferably ice-cooling to room temperature, for 1 to 16 hours.
Acid anhydrides (especially, mixed acid anhydrides), acid halides, acid azides, and esters can be utilized in this reaction as a reactive derivative of compound (Ia-1). These reactive derivatives are produced by usual methods. For example, the acid anhydride derivatives can be produced by a reaction of compound (Ia-1) with acid halide derivatives (e.g., ethyl chlorocarbonate) in the presence of a base (e.g., triethylamine), and acid halide derivatives can be produced by a reaction of compound (Ia-1) with a halogenation agent (e.g., oxalylchloride, and thionylchloride). Ester derivatives may be inactive or active. Sulfonyl derivatives converted from a compound (XV) wherein R15 is a carboxyl protective groups (e.g., methyl, tert-butyl, and benzyl) at process 1 can be used as inactive esters without deprotection. Active esters can be produced by a reaction of compound (Ia-1), carbodiimide reagents (e.g., dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), and hydroxy derivatives corresponding to the active ester residue such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, or the like. A reaction condition of conversion of the reactive derivatives of compound (Ia-1) to hydroxamic acid may be the same as that of conversion of compound (Ia-1) itself to hydroxamic acid. The reactions of processes 1 and 2 are able to continuously be carried out in one-pot reaction.
(Process 3)
A protected hydroxylamine to be used in this reaction includes O-benzylhydroxylamine, O-(p-methoxybenzyl)hydroxylamine, O-(tert-butyl)hydroxylamine, or the like. This reaction condition may be in the same manner as that of process 2.
(Process 4)
This process for deprotection is carried out by catalytic reduction, treatment with conc. hydrochloric acid, or treatment with trifluoroacetic acid to give the desired compound (Ib-1). The compounds of this invention (Ia-1) and (Ib-1) can be isolated and purified by usual separation methods and purification methods (e.g., chromatography, crystallization, etc.).
(Method B) 
wherein R1, R2, R7, R15, and Hal are as defined above, R17 is optionally substituted aryl or optionally substituted heteroaryl.
Conversion of compound (XV) to compound (XVII) is performed by sulfonation of an amino group of compound (XV) (process 1) in the same manner as that described in process 1 of method A. Conversion of compound (XVII) to compound (XVIII) is performed by Heck reaction (K. Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron Lett., 4467(1975) etc.) wherein halogen of R17 is utilized to insert a triple bond (process 2). Conversion of compound (XVIII) to compound (Ia-2) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 3), which can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-2) to compound (Ib-2) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 4), which can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.
(Process 1)
This process may be carried out in the same manner as that described in process 1 of method A.
(Process 2).
Compound (XVII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having an ethynyl group such as ethynylbenzene in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(Ph3P)2Cl2), a divalent copper reagent (e.g., CuI), and an organic base (e.g., triethylamine, and diisopropylethylamine) to give a desired compound (XVIII) (Heck reaction). This reaction is carried out at room temperature to 100xc2x0 C., preferably room temperature to 80xc2x0 C. This reaction is completed for 3 to 30 hours, preferably 10 to 20 hours. When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (Theodora W. Green (John Wiley and Sons)), and then deprotected at an appropriate step.
(Process 3)
This process may be carried out in the same manner as that described in process 1 of method A.
(Process 4)
This process may be carried out in the same manner as those described in processes 2 to 4 of method A. 
wherein R1, R2, R7, R15, R17, and Hal are as defined above.
Conversion of compound (XVII) to compound (XIX) is performed by Suzuki reaction (M. J. Sharp and V. Shieckus, Tetrahedron Lett., 26, 5997 (1985) etc.) wherein halogen of R17 is utilized to introduce aryl or heteroaryl (process 1). Conversion of compound (XIX) to compound (Ia-3) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 2) and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-3) to. compound (Ib-3) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 3), and this process can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.
(Process 1)
Compound (XVII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having a B(OH)2 (otherwise B(Et)2) group such as phenylboronic acid in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(Ph3P)4) and a base (e.g., potassium carbonate, calcium carbonate, triethylamine, sodium methoxide etc.) to give the desired compound (XIX) (Suzuki reaction). This reaction is carried out at room temperature to 100xc2x0 C., preferably room temperature to 80xc2x0 C. This reaction is completed for 5 to 50 hours, preferably 15 to 30 hours. When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (Theodora W. Green (John Wiley and Sons)) and then deprotected at an appropriate step.
(Process 2)
This process may be carried out in the same manner as that described in process 1 of method A.
(Process 3)
This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
(Method D) 
wherein R1, R2, R7, R15, R17, and Hal are as defined above.
Conversion of compound (XV) to compound (XX) is sulfonation of an amino group of the compound (XV) (process 1) and this process may be carried out in the same manner as that described in process 1 of method A. Conversion of compound (XX) to compound (XXI) is reduction of a nitro group of R17 to an amino group (process 2) and this process can be carried out by catalytic reduction or other reduction using hydrochloric chloridexe2x80x94Fe, hydrochloric chloridexe2x80x94Sn, etc. Conversion of compound (XXI) to compound (XXII) is performed by usual amide bond formation reaction wherein an amino group of R17 is utilized (process 3). Conversion of compound (XXII) to compound (Ia-4) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 4) of compound (XXII) and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-4) to compound (Ib-4) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 5) and this process can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.
(Process 1)
This process may be carried out in the same manner as that described in process 1 of method A.
(Process 2)
Compound (XX) is treated with hydrogen in a solvent such as methanol, ethanol, ethyl acetate, acetic acid, etc. in the presence of a catalyst (e.g., Pdxe2x80x94C, PtO2, Raney Ni etc.), under a no-pressure or pressured condition to give the desired compound (XXI). This reaction is carried out at a temperature under ice-cooling to 80xc2x0 C., preferably room temperature to 50xc2x0 C., and is completed for 1 to 10 hours, preferably 2 to 5 hours.
(Process 3)
Compound (XXI) is reacted with optionally substituted aryl or optionally substituted heteroaryl having an acid halide (otherwise an active ester) group such as benzoyl chloride in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, xylene, toluene, benzene, dichloromethane, etc. in the presence of a base (e.g., triethylamine, N-methylmorpholine, potassium carbonate etc.) to give the desired compound (XXII). This reaction is carried out at a temperature under ice-cooling to 100xc2x0 C., preferably room temperature to 60xc2x0 C., and is completed for 3 to 30 hours, preferably 10 to 25 hours.
(Process 4)
This process may be carried out in the same manner as that described in process 1 of method A.
(Process 5)
This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
(Method E) 
wherein R1, R2, R7, R15, R17, and Hal are as defined above.
Conversion of compound (XV) to compound (XXIII) is performed by sulfonating an amino group of the compound (XV) (process 1) in the same manner as that described in process 1 of method A. Conversion of compound (XXIII) to compound (XXIV) is done by the reduction wherein an ethenyl group of R17 is converted into an aldehyde group (process 2). Conversion of compound (XXIV) to compound (XXVI) is performed by a tetrazole ring formation reaction (processes 3 and 4). Conversion of compound (XXVI) to compound (Ia-5) is N-alkylation, deprotection of a carboxyl protective group, etc. of compound (XXVI) (process 5), and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-5) to compound (Ib-5) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 6), which can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.
(Process 1)
This process may be carried out in the same manner as that described in process 1 of method A.
(Process 2)
A compound (XXIII) is treated with ozone in a solvent such as dichloromethane, ethyl acetate, methanol, etc. to form an ozonide, and then a reagent such as zinc-acetic acid, triethylphosphate, dimethylsulfide, etc. is added to this reaction mixture for reduction to give the desired aldehyde derivatives (XXIV) The reduction can also be carried out by catalytic hydrogenation. This reaction is carried out at xe2x88x92100xc2x0 C. to room temperature, preferably xe2x88x9278xc2x0 C. to a temperature under ice-cooling, and is completed for 0.5 to 10 hours, preferably 1 to 3 hours.
(Process 3)
A compound (XXIV) is reacted with benzensulfonylhydrazide in a solvent such as tetrahydrofuran, ether, etc. mixed with a solvent such as methanol, ethanol, etc. to give the desired compound (XXV). This reaction is carried out at a temperature under ice-cooling to 80xc2x0 C., preferably room temperature to 50xc2x0 C., and is completed for 3 to 30 hours, preferably 10 to 20 hours.
(Process 4)
Optionally substituted aryl or optionally substituted heteroaryl having amino group such as aniline is dissolved in a mixed solvent such as alcohol (e.g., ethanol) and water. To this mixture conc. hydrochloric acid and a diazotizing agent such as a sodium nitrite aqueous solution are added at xe2x88x9220xc2x0 C. to 10xc2x0 C., preferably 0xc2x0 C. to 5xc2x0 C., to give a diazonium salt. The reaction time is 5 min to 1 hr, preferably 10 to 30 min. This reaction mixture is added to a pyridine solution of compound (XXV) and allowed react for 1 to 10 hr, preferably 2 to 5 hr, at xe2x88x9230xc2x0 C. to 50xc2x0 C., preferably xe2x88x9215xc2x0 C. to room temperature to give the desired compound (XXVI). When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of a xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (Theodora W. Green (John Wiley and Sons)), and then deprotected at an appropriate step.
(Process 5)
This process may be carried out in the same manner as that described in process 1 of method A.
(Process 6)
This process may be carried out in the same manner as those described in processes 2 to 4 of method A. 
wherein R1, R2, R7, R15, R17, and Hal are as defined above.
Conversion of compound (XXIV) to compound (XXVII) is performed by Wittig reaction (G. Wittig et al., Chem. Berr. 87, 1318 (1954)) wherein an aldehyde group of R17 is utilized to introduce aryl or heteroaryl through a double bond (process 1). Conversion of compound (XXVII) to compound (Ia-6) is N-alkylatibn, deprotection, etc. of compound (XXVII) process 2), and this process can be carried out the same similar as described in process 1 of method A. Conversion of compound (Ia-6) to compound (Ib-6) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 3), and this process can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.
(Process 1)
Compound (XXIV) is reacted with ylide derivatives of optionally substituted aryl or optionally substituted heteroaryl such as Ph3Pxe2x95x90CHPh, etc., which is produced by an usual method, in a solvent such as toluene, xylene, tetrahydrofuran, ether, dimethylformamide, etc. at xe2x88x92100 to room temperature, preferably xe2x88x9278xc2x0 C. to ice-cooling for 1 to 20 hours, preferably 1 to 5 hours, to give the desired compound (XXVII). When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (Theodora W. Green (John Wiley and Sons)), and deprotected at an appropriate step.
(Process 2)
This process may be carried out in the same manner as that described in process 1 of method A.
(Process 3)
This process may be carried out in the same manner as those described in processes 2 to 4 of method A.
The term xe2x80x9ccompound of the present inventionxe2x80x9d herein used includes pharmaceutically acceptable salt or hydrate of the compound. The salt is exemplified by a salt with alkali metals (e.g., lithium, sodium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid), or organic acids (e.g., acetic acid, citric acid, mallein acid, fumaric acid, benzenesulfonic acid, and p-toluenesulfonic acid). These salts can be formed by the usual method.
The compound of the present invention is not restricted to any particular isomers but includes all possible isomers and racemic modifications.
The compound of the present invention has an excellent activity for inhibiting metalloproteinase, especially activity for inhibiting MMP, and inhibits matrix dissolution, as described in the following test example. Therefore, the compound of the present invention is useful to treat or prevent diseases which are caused by MMP and relative enzymes such as TNF-xcex1 converting enzyme, etc.
Definitely, the compounds of the present invention are useful in the prevention or treatment of diseases such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced virus infection (e.g., HIV), arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis, multiple sclerosis, open angle glaucoma, retinopathies, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes, nephritis, neurodegengerative disease, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, Crohn disease, meningitis, and gastric ulcer.
When the compound of the present invention is administered to a person for treatment or prevention of the above diseases, they can be administered by oral administration such as powder, granules, tablets, capsules, pilulae, and liquid medicine, or by parenteral administration such as injections, suppository, percutaneous formulations, insufflation, or the like. An effective dose of the compound of the invention is formulated by being mixed with medicinal admixture such as excipient, penetrant, disintegrators, lubricant, and the like if necessary. When parenteral injection is prepared, the compound of the invention and an appropriate carrier are sterilized to prepare it.
An appropriate dosage varies with the conditions of the patients, an administration route, their age, their body weight and the like and should be determined by a physician in the end. In the case of oral administration, a daily dosage can generally be between 0.1-100 mg/kg/day, preferably 1-20 mg/kg/day. In the case of parenteral administration, the daily dosage can generally be between 0.01-10 mg/kg/day, preferably 0.1-1 mg/kg/day. The daily dosage can be administrated in one to several divisions.